A Systematic Literature Review of Complementary and Alternative Veterinary Medicine: Laser Therapy

Simple Summary Light therapy, or photobiomodulation, is a collective name for methods where tissue is irradiated with different types of light, with the aim of stimulating healing. The group includes methods such as laser, Light Emitting Diode (LED) light, ultra and infrared light, and tanning beds. In animals, the main indications for light treatment are musculoskeletal injuries, neurological diseases, wounds, and pain. Despite being frequently used, there is no consensus regarding the optimal treatment protocols for light therapy nor its clinical efficacy. Therefore, the aim of this systematic review was to evaluate the documented clinical effects of light therapy, with a focus on laser and LED light, in horses, dogs, and cats. The undertaken systematic literature review found gaps in the scientific documentation. Conflicting study results and unclear application for clinical use are explained by the wide variety of treatment parameters used in the analyzed studies, such as wavelength, laser class, dose, and effect, as well as the frequency and duration of treatment. Some beneficial effects have been reported during treatment with light therapy; however, the published studies also have limited scientific quality regarding these therapies, with a high or moderate risk of bias. Abstract Light therapy, or photobiomodulation, is a collective name for methods where tissue is irradiated with different types of light, with the aim of stimulating healing. Despite being frequently used, there is no consensus regarding the optimal treatment protocols for light therapy, nor its clinical efficacy. A systematic literature review was conducted, searching the relevant literature regarding light therapy in three databases, published between 1980–2020. The risk of bias in each article was evaluated. Forty-five articles met the inclusion criteria; 24 articles were regarding dogs, 1 was regarding cats, and the rest were regarding horses. The indications for treatment were musculoskeletal and neurologic conditions, skin disease and wounds, and pain. The literature review showed conflicting study results and unclear application for clinical use. This can be explained by the wide variety of treatment parameters used in the searched studies, such as wavelength, laser class, dose, and effect, as well as the frequency and duration of treatment. Although some beneficial effects were reported for light therapy, the studies also had limited scientific quality regarding these therapies, with a high or moderate risk of bias.


Introduction
Light therapy, or photobiomodulation, is a collective name for methods where tissue is irradiated with different types of light, with the aim of stimulating healing. The group includes methods such as laser, Light Emitting Diode (LED) light, ultra and infrared light, and tanning beds. In humans, light therapy has been used for decades to treat various conditions such as depression, skin disease and wounds, and pain, as well as to promote the

Materials and Methods
The overall outline of this systematic review adhered to the Cochrane guidelines regarding how to perform a systematic review [4], as adapted by the Swedish Agency for Health Technology Assessment and Assessment of Social Services (SBU) in its methodological handbook [5].

Review Topic/Research Question
To assess the evidence for the clinical efficacy of laser and LED therapy used in horses, dogs, and cats.

Search Strategy
Professional librarians searched the literature in the databases Web of Science Core Collection, CABI, and PubMed  in August 2020. The keywords were terms relevant to dog OR cat OR horse, AND veterinary medicine OR veterinarian, AND therapy * OR treatment *. These keywords were combined with terms related to light therapies, i.e., laser therapy, therapeutic laser, cold laser, low-level laser or photobiomodulation, and light emitting diode.

General Inclusion and Exclusion Criteria
The included studies were to be original research, which was published in a peerreviewed journal between years 1980-2020. Primarily observational studies that would have only one method studied per treatment group were included. Experimental studies could also be included when the study mimicked a clinical situation. The subject species were to be either canine, feline, or equine.
Textbook chapters, conference proceedings, abstracts, opinion notes, review articles, and case reports (subject number < 5) were excluded. Mechanism of action experimental studies were also excluded, along with studies that used multiple treatments simultaneously per intervention group.

Study Selection and Categorisation
All screening was performed based on journal title, publication title, or abstract. Citations identified were imported into Endnote (X9. 3.3, 2018) and duplicates were removed. A single author (DM) applied inclusion and exclusion criteria to all publications.
In the screening phase, articles of possible relevance for the review, and articles describing one type of intervention in cats, dogs, or horses were selected for full text reading. A therapeutic intervention was defined as an intervention intended to reduce the signs, severity, or duration of a clinical condition. After the first stage of screening, articles deemed potentially relevant were accessed. For each study, the following key descriptive items were tabulated using templates modified after SBU [5]: first author, year of publication, study design, study population, intervention, and type of control, outcome, and relevance (external validity).
Assessment of the risk of bias (scientific quality) of each article was performed in accordance with the Cochrane [4] and SBU [5] guidelines. The assessment was based on the following items: study design, statistical power, deviation from planned therapy, loss to follow-up, type of outcome assessment, and relevance. In the assessment of observational studies, risk of confounding was also included. The writing of the paper has been conducted following the PRISMA 2022 checklist and the study has not been registered in PROSPERO since it is not for human health.

Results
A total of 2581 abstracts were identified from the three electronic databases (Figure 1). Duplicates were removed and the abstracts were re-evaluated using the inclusion criteria. A total of 125 publications were studied in detail. Regarding laser treatment of the musculoskeletal system, 50 studies were identified, of which 28 were dog studies, 22 were on horses, and none were cat studies. Thirteen of these met the inclusion criteria. Regarding the effects of laser on skin and wound healing, 44 abstracts were identified, of which 32 were dog studies, 12 were studies of horses, and none were regarding cats. Nineteen of these met the inclusion criteria. In the treatment of pain with laser, three studies were regarding dogs, one was regarding cats, and six studies were on horses. Seven of these were included. Of 20 dog studies regarding laser treatment for various neurological conditions, 6 studies met the inclusion criteria. A horse study was identified; however, it did not meet the inclusion criteria. The studies that did not meet the inclusion criteria were case reports, review articles, method articles, or had phototherapy as part of a combination of treatments, which made the evaluation of phototherapy as a single treatment impossible.

Study Quality
In general, the quality of the studies was low. In many cases, details regarding laser application were missing or inadequate, controls groups were not included, or other interventions were administered along with laser therapy.

General Clinical Indications
Photobiomodulation is used in a variety of applications in veterinary medicine, including musculoskeletal conditions, skin and wound healing, neurological conditions, pain, and a variety of other indications.

Intervention, Control and Clinical Effects
Of the 13 articles on musculoskeletal conditions, 8 had a low risk of bias, 3 a moderate, and 2 a high (Table 1). Of the six studies which evaluated laser for musculoskeletal conditions in dogs, four were randomized, controlled trials (RCT), and three of these showed possible benefits. A study of laser for elbow arthritis indicated improvement in subjective parameters and reduction in the use of non-steroidal anti-inflammatory drugs, evaluated by the dog owner [6]. The laser dose was based on body weight. Three studies evaluated the use of laser treatment in dogs that underwent a tibial plateau leveling osteotomy (TPLO) for cranial cruciate ligament injury. A preoperative treatment was mildly effective in improving post-operative weight bearing, evaluated by force platform measurement [7]. A larger RCT study indicated improvement in lameness via a subjective scoring system; however, no objective methods were used [8]. A study of dogs treated for eight weeks after TPLO used a combination of subjective and objective measures. The study found no significant differences between the treated and placebo groups, with better results observed for the placebo group than the treated dogs at several time points [9].
A research study on osteogenesis reported positive effects of laser treatment on bone formation and healing time of the osteotomy [10]. Interestingly, the TPLO studies also evaluated bone healing, and none of them showed a positive effect. An uncontrolled study of laser treatment for osteomyelitis, after unsuccessful treatment with antibiotics, indicated a positive result in most dogs; however, long-term follow-up was not performed [11].

Musculoskeletal Conditions Intervention, Control and Clinical Effects
Of the 13 articles on musculoskeletal conditions, 8 had a low risk of bias, 3 a moderate, and 2 a high (Table 1). Of the six studies which evaluated laser for musculoskeletal conditions in dogs, four were randomized, controlled trials (RCT), and three of these showed possible benefits. A study of laser for elbow arthritis indicated improvement in subjective parameters and reduction in the use of non-steroidal anti-inflammatory drugs, evaluated by the dog owner [6]. The laser dose was based on body weight. Three studies evaluated the use of laser treatment in dogs that underwent a tibial plateau leveling osteotomy (TPLO) for cranial cruciate ligament injury. A preoperative treatment was mildly effective in improving post-operative weight bearing, evaluated by force platform measurement [7]. A larger RCT study indicated improvement in lameness via a subjective scoring system; however, no objective methods were used [8]. A study of dogs treated for eight weeks after TPLO used a combination of subjective and objective measures. The study found no significant differences between the treated and placebo groups, with better results observed for the placebo group than the treated dogs at several time points [9]. A research study on osteogenesis reported positive effects of laser treatment on bone formation and healing time of the osteotomy [10]. Interestingly, the TPLO studies also evaluated bone healing, and none of them showed a positive effect. An uncontrolled study of laser treatment for osteomyelitis, after unsuccessful treatment with antibiotics, indicated a positive result in most dogs; however, long-term follow-up was not performed [11].
Seven of the horse studies were RCT. Two studies evaluated carbon dioxide laser for acute traumatic arthritis of the fetlock joint. One study, without an untreated control group, compared betamethasone and hyaluronan with carbon dioxide laser for acute traumatic arthritis, with a more favorable recovery in the laser-treated group [12]. A smaller study, which evaluated laser treatment compared to a control group, showed no differences in subjective lameness assessment, objective movement analysis with accelerometry, and analysis of inflammatory markers in the synovial fluid [13].
Other equine studies largely evaluated the effect of laser on tendon or ligament injuries. A clinical study of horses with ligament or tendon injuries indicated improved edema, lameness, and lesion size; however, no differences in healing were detected with objective ultrasound evaluations [14]. A retrospective study of a large number of horses with superficial digital flexor tendon injuries showed no advantage of laser treatment compared to conservative treatment [15].
Other studies evaluated the penetration ability or thermal effects of lasers on equine tissue. An experimental study of carbon dioxide laser showed increased skin perfusion and temperature in treated horses, with the biggest changes occurring in horses with clipped hair [16]. However, there were no temperature or perfusion differences in deeper tissues. Another study of laser application also showed increased skin temperature, which was assessed with a thermal imager [17]. A study of near-infrared lasers on cadaveric superficial digital flexor tendons indicated poor light penetration into the tissue [18].

Skin and Wound Healing Intervention, Control and Clinical Effects
Of the 19 articles on skin and wounds, 11 had a low risk, 6 had a moderate, and 2 had a high risk of bias (Table 2). Of the 10 dog studies, one randomized controlled trial (RCT) showed potential benefit in wound healing properties. Most of the studies evaluated wound healing or absorbance of laser energy in the tissue. Three well-controlled blinded studies showed no effect of laser treatment on wound healing in surgically-created sutured or open wounds [19][20][21], while one study showed a slightly faster healing time with improved scarring after laser treatment [22]. One study on infected wounds showed no effect of laser treatment [23], while another that used blue light showed improvement of pyoderma in dogs [24]. A study of pedal pruritus due to atopy showed no effect of laser treatment [25].
Studies of laser penetration indicated that if the laser head has contact with the skin, there is better light penetration than when applied without contact [26]. Other aspects that improved light penetration in tissues were clipped hair, and lighter skin color [27]. Most laser energy was found to be absorbed by the superficial tissues. Other studies included the use of lasers to treat aural hematomas [28] and alopecia [29]; these studies indicated a positive effect; however, the design of the studies used subjective outcome measures or had inadequate controls, which left interpretation of the results questionable.   There was greater penetration in cervical skin with the superpulsed laser than the class IV laser. There was also greater penetration in light skin horses All eight of the horse studies were RCT, with most studies being either tissue penetration of laser light or wound healing, and with two wound healing studies showing no effect and two showing some positive effects. Two well-controlled studies showed no effect of laser on wound healing [30,31], while two indicated an improvement in wound healing of tissue in the pharynx [32] and granulation tissue on the extremities compared with bandages or basic liniments [33]. One study suggested that a very high doses of laser energy may damage tissues [34] (Bergh A, 2007). Three studies evaluated laser penetration into tissues, with most laser energy absorbed by very superficial tissues, similar to the canine studies [35][36][37]. Clipping and cleansing the skin improved penetration, and one study showed better penetration in light horses [37], while another showed no effect of skin color [36].

Pain Intervention, Control and Clinical Effects
In the treatment of pain with laser, three dog, one cat, and six horse studies were identified (Table 3). Of these, one dog, one cat, and five horse studies met the inclusion criteria, and of these seven articles, none had a low risk, three had a moderate, and four had a high risk of bias. A study of dogs undergoing treatment for pain after ovariohysterectomy with laser acupuncture suggested an improved pain relief compared to meloxicam [38]. A similar study of pain relief after ovariohysterectomy was also performed in cats [39]. Although laser acupuncture and electroacupuncture were similar in the treatment of pain, both treatments required fewer rescue analgesics compared to placebo. Three horse studies evaluated laser treatment for back pain. one study had no controls; therefore, no conclusions could be drawn about its effect [40]. The other two suggested positive results regarding the use of laser for the treatment of back pain [41,42]. An uncontrolled study of laser treatment for laminitis indicated an improvement; however, no conclusions could be drawn [43]. Another laser study in horses treated with epidural anesthesia suggested that laser treatment prolonged analgesia with concomitant epidural anesthesia [44].

Neurological Conditions Intervention, Control and Clinical Effects
Of 20 canine studies regarding photobiomodulation for neurologic conditions, six met the inclusion criteria, with one having a low, three a moderate, and two a high risk of bias (Table 4). Only one of the four studies of laser for the postoperative treatment of intervertebral disk disease [45][46][47] showed a positive effect [48]. However, the dose of laser used in that study was unclear. Another experimental study of sciatic nerve injury indicated an improvement in EMG activity after laser treatment [49]. A study of laser use in treating degenerative myelopathy did not have a control group (comparison to a historical control group was used), had other confounding factors that may have influenced the results, and the laser dose used to compare Class III and Class IV lasers was not the same [50].

Discussion
In this systematic literature review, 45 studies were identified and evaluated in which light therapy was used to treat musculoskeletal and neurologic conditions, skin and wounds, and pain, in dogs and horses, as well as ovariohysterectomy in cats.
Of the 13 articles on musculoskeletal conditions, 4 experimental studies investigated tissue temperature changes and light penetration depths [10,[16][17][18]. The studies with a low risk of bias had conflicting results, varying from positive effects on weight distribution and pain scores, to no significant differences. Of the 19 articles on skin and wounds, the majority were experimental studies investigating the healing of surgically-created wounds, skin and hair characteristics affecting laser penetration, and light penetration depths. The studies with a low risk of bias showed no significant differences in quality or rate of wound healing. Of the seven articles on pain, all were clinical studies, with some suggesting some benefit regarding pain relief.
Finally, of the six articles regarding neurologic conditions, laser treatment had mixed benefits. The single study with a low risk of bias reported no significant differences in time to reach recovery or duration of postoperative IV opioid administration following intervertebral disk herniation surgery [46]. One experimental study evaluated the effect of laser therapy after experimental crush sciatic nerve injury and suggested some benefit [49].
The reasons for the studies' risks of bias, which make it difficult to draw certain conclusions from the literature review results, are several. In the evaluated studies, the small groups of animals were consistently a major source of a high risk of bias, as well as studies where control groups were missing or where people who evaluated/made measurements on the animals were aware of the treatment given. Study groups with individuals of different ages, genders, and breeds could also contribute to a large spread of the results. The design of some of the studies was of insufficient quality to convince the research and veterinary scientific communities to accept (or discard) the therapy. Additionally, a major reason for the difficulty in drawing any firm conclusions is the heterogeneity of the treatment protocols. Despite the majority of studies looking at therapeutic laser therapy, the included studies used different types of lasers, with different wavelengths. Further, there was no agreement regarding dose and treatment time, and in many cases, the treatment parameters were not fully described. Considering the heterogeneity between studies and the low number of studies for each combination of species and indication, pooled statistical analysis with meta-analysis was not feasible. With many small studies, the possibility of publication bias increases; small studies with a negative outcome are less likely to be published [51]. The methods to detect and adjust for publication bias require that there are at least some larger studies to be used as a reference [52]. This made it impossible to conduct any further statistical analyses on the material.
When a method is introduced to veterinary medicine, it is important to know its clinical effects for its proposed indications. Before a sufficient number of studies have been conducted, and a meta-analysis of the effects performed, it is important to have knowledge of the method's mode of action and application. The results of this literature review suggest that several factors may affect this proposed mechanism of action; the penetration depth of light depends on the wavelength of the laser, if the hair coat is clipped or not, and the type of tissue that is irradiated. The fact that some lasers may cause an increase in tissue temperature, and subsequent increase in blood flow [16,17], may be positive for healing processes; however, it may also pose an increased risk of injury [34]. It is also possible that the influence of light therapy, with a focus on the laser, on tissue effects depends on the total dosage of laser radiation used, and the time and method of radiation. It has been suggested that radiation in the early stages of healing, and repeated radiation over a certain period, could have different amounts of effectiveness on tissues such as bone [53].

Conclusions
The systematic literature review undertaken in this study found a general lack of quality evidence in the scientific documentation regarding the clinical effects of laser and LED light therapy in horses, dogs, and cats. For most of the indications, there was insufficient scientific evidence for favorable clinical effects; the studies were (a) negative or (b) of insufficient quality, or (c) the results were contradictory or (d) confirmatory results were lacking. Although some beneficial effects have been reported for laser therapy, the conflicting study results and unclear application for clinical use are explained by the wide variety of treatment parameters used in the studies, such as wavelength, laser class, dose and effect, and the frequency and duration of treatment. In many cases, the description of phototherapy use was incomplete, such as the dose used.
Although potential mechanisms of action have been evaluated in tissue and cell culture, as well as some live animal experiments, clinical trials to evaluate the efficacy and proper use of light therapy must be conducted prior to its widespread application for clinical use. Moving forward, multi-institutional studies evaluating a large number of patients with strict inclusion criteria for various conditions and complete description of the application of light therapy are recommended. Additionally, dose titration studies are needed to determine the optimal dose, power, and frequency of light therapy for clinical use.